OMIM ID:
Niemann-Pick Disease, Types C1 (D)
Alternate Names
Defective Genes
Clinical Characteristics
Ocular Features
The predominant ocular sign in types C1 is difficulty in upgaze described as a supranuclear palsy. Abnormal saccadic movements have been reported as well. Retinal signs such as a cherry red spot are not common.
Systemic Features
Hepatosplenomegaly and cognitive decline are similar in nature to those found in Niemann-Pick disease types A and B. Types C1 and C2 are clinically similar but discussed separately as they are caused by mutations in separate genes. Type D is caused by the same mutation causing C1. Onset of disease manifested by ataxia, seizures and spasticity is usually between 2 and 4 years. Dystonia, intention tremor, dysarthria, and hepatosplenomegaly are other features but visceral involvement may be absent. Ascites and jaundice are sometimes present. Dementia and extrapyramidal signs are often seen later. However, there is considerable variation in onset and progression of disease but the symptoms are generally milder than that in types A and B.
Genetics
Inheritance
Type C1 (and D) are caused by mutations in the NPC1 gene (18q11-q12), and type C2 (607625) by mutations in the NPC2 gene (14q24.3). Mutations in C1 are far more common (95%) than C2 mutations. The gene mutations reduce the efficiency of sphingosine efflux from lysosomes and late endosomes as a result of a defect in esterification of cholesterol.
Types A (257200) and B (607616) Niemann-Pick disease generally cause more severe clinical signs and are the result of a sphingomyelinase deficiency. All types of Niemann-Pick disease follow autosomal recessive patterns of inheritance.
Pedigree
Autosomal recessive
In order for autosomal recessive disorders to be expressed, offspring generally must inherit two mutations, one from each carrier parent. Carriers with only one mutation, such as the parents, do not have clinical disease. Note that carrier parents can expect that 1 in 4 children (25%) will inherit both mutations and have the disorder, 2 in 4 children (50%) will be carriers like their parents, while 1 in 4 children (25%) inherit neither mutation.
In order for autosomal recessive disorders to be expressed, offspring generally must inherit two mutations, one from each carrier parent. Carriers with only one mutation, such as the parents, do not have clinical disease. Note that carrier parents can expect that 1 in 4 children (25%) will inherit both mutations and have the disorder, 2 in 4 children (50%) will be carriers like their parents, while 1 in 4 children (25%) inherit neither mutation.